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PubMed2026

Genomic dimensions deconstruct the clinical heterogeneity of bipolar disorder.

Bipolar disorder's (BD) clinical heterogeneity has an unresolved genetic basis. We meta-analyzed genome-wide association studies (GWAS) of 16 BD subphenotypes in 226,032 individuals from 57 cohorts (38,022 cases); 10 advanced to multivariate and multi-trait analyses. Four factors (compulsive, psychotic, dysregulated, internalizing) explained 82.8% of shared genetic variance. BD1 and BD2 loaded on distinct factors despite a high genetic correlation; 87.0% of common-factor loci were significant in neither subtype. Unipolar mania aligned with psychosis over internalizing, and was distinguishable from BD1, and rapid cycling showed heritable cross-domain liability. We identified 356 risk loci, 158 novel, including the first univariate-GWAS associations for psychosis, unipolar mania, rapid cycling and schizoaffective disorder-and 249 credible genes (89 high-confidence), 12 with approved-drug or clinical-phase annotations. Cell-type association showed a midbrain dopaminergic-GABAergic gradient along the psychotic factor. BD's genetic architecture appears hierarchical-a general liability resolving into dimensions of course and comorbidity, beyond subtypes.

Journal Article↗

PubMed1996

Case study: comorbidity among Tourette's syndrome, autistic disorder, and bipolar disorder.

OBJECTIVE: Several studies report a greater than expected concurrence for Tourette's syndrome (TS) with autistic disorder (AD). TS and bipolar disorder (BD) also may co-occur at a greater than expected rate. The authors assess whether there is a greater than expected concurrence for TS+AD+BD. METHOD: Four patients who had at some time in their lives diagnoses of TS, AD, and BD were identified. Three of these had concurrent TS+AD+BD. Diagnoses were made according to DSM-III-R criteria. Each of these patients was living in North Dakota and was in the authors' care at the time of this study. RESULTS: The point prevalence (risk) for concurrent TS+AD+BD in North Dakota is not less than 4.6 x 10(-6). The developmental sequence of syndromes in these four patients was AD, then TS and then BD. Data from the authors' previously published, population-based prevalence studies indicate that TS+AD+BD co-occur at a greater than chance expectation. CONCLUSIONS: Common etiological factors may be involved in the greater than chance concurrence of TS+AD+BD.

Adolescent↗

PubMed2001

Bipolar disorder, schizoaffective disorder and schizophrenia: epidemiologic, clinical and prognostic differences.

The validity and nosologic status of schizoaffective disorder is still a controversial issue. This study was conducted to analyze the demographic, clinical and prognostic variables that determine the validity of the diagnosis of schizoaffective disorder bipolar type. We analyzed and compared 138 outpatients: 67 with type I bipolar disorder, 34 with schizoaffective disorder bipolar type and 37 with schizophrenia. They were all diagnosed following research diagnostic criteria and assessed according to the Schedule for Affective Disorders and Schizophrenia. Schizoaffective unipolar patients were excluded. The results reaffirmed that, from the standpoints of demographics, clinical features and prognosis, schizoaffective disorders bipolar type can be classified as a phenotypic form at an intermediate point between bipolar I disorder and schizophrenia. These results emphasize the importance of longitudinal follow-up in the diagnosis and assessment of psychotic syndromes. Although cross-sectional symptoms were closer to the schizophrenia spectrum, the course of the illness resembled more that of bipolar patients, resulting in an intermediate outcome.

Adolescent↗

PubMed2006

Obsessive-compulsive disorder in bipolar disorder patients with first manic episode.

BACKGROUND: Evidence indicates that obsessive--compulsive disorder (OCD) co-occurs with schizophrenia and bipolar disorder (BD) at a higher rate than in the general population. The inflated rate of comorbidity may result from chronic illness, antipsychotic therapy or treatment-seeking behavior. To control for these factors we evaluated the prevalence of OCD in patients with first-episode acute mania who met DSM-IV criteria for BD-I, and compared them with our previously reported group of first-episode schizophrenia patients. METHOD: Fifty-six BD-I patients with a first-episode of acute mania were screened for OCD and additional comorbid disorders using the Structured Clinical Interview for DSM-IV Axis-I disorders and appropriate rating scales. RESULTS: Only one patient (1.8%) met DSM-IV criteria for OCD, and two (3.6%) met criteria for sub-threshold OCD. In contrast, there was a substantial aggregation of substance use disorders 32.1% (N=8), anxiety disorders, other than OCD 26.8% (N=15) and eating disorders 14.3% (N=8). LIMITATIONS: Small sample size, cross-sectional nature of the assessments and the inclusion of only BD-I patients. CONCLUSION: The rate of OCD in first-episode BD-I patients did not differ significantly from that found in the general population and was substantially lower than in previously reported first-episode schizophrenia patients (1.8% vs. 14%). We suggest that a preferential association of OCD with schizophrenia early in the course of illness represents a pathophysiological linkage between the two disorders, and putatively a specific schizo-obsessive subtype. In contrast, OCD in BD-I may stand for "true" comorbidity. Large-scale parallel comparative evaluations of comorbidity in BD-I and schizophrenia may contribute to the search for specific pathophysiological mechanisms of distinct comorbid-related subsets in either disorder.

Acute Disease↗

PubMed2006

Anxiety disorders and bipolar disorder: a review.

CONTEXT: Epidemiological, clinical and familial studies indicate that anxiety disorders (ADs) are highly comorbid in persons with bipolar disorder (BPD). The phenomenological overlap between ADs and BPD is reported more frequently in individuals with female predominant bipolar presentations (e.g., bipolar II disorder). Anxiety comorbidity in the BPD population poses a serious hazard. For example, it is associated with an intensification of symptoms, non-recovery, substance use comorbidity and harmful dysfunction (e.g., suicidality). OBJECTIVE: The evidentiary base informing treatment decisions for the anxious bipolar patient is woefully inadequate. Several expert consensus and evidence-based treatment guidelines for BPD suggest various treatment avenues, although these have been insufficiently studied. The encompassing aim of this paper is to synthesize extant studies reporting on the co-occurrence of AD and BPD. Taken together, a compelling basis emerges for prioritizing the identification and management of anxiety symptomatology in the BPD population.

Anxiety Disorders↗

PubMed2003

Clozapine in treatment-resistant patients with schizophrenia, schizoaffective disorder, or psychotic bipolar disorder: a naturalistic 48-month follow-up study.

BACKGROUND: The aim of this study was to evaluate the long-term efficacy and safety of clozapine in patients with treatment-resistant schizophrenia, schizoaffective disorder, or bipolar disorder with psychotic features. METHOD: 101 patients with a DSM-III-R diagnosis of schizophrenia (N = 34); schizoaffective disorder, bipolar type (N = 30); or bipolar disorder with psychotic features (N = 37) were naturalistically treated with clozapine at flexible doses over a 48-month period. Data were collected from 1994 to 2000. The Brief Psychiatric Rating Scale (BPRS) and Clinical Global Impressions-Severity of Illness scale total predicted scores over time were estimated with random-effects regression models. Time to response to clozapine, defined as 50% reduction of BPRS score, was analyzed in the 3 diagnostic groups using the Kaplan-Meier method. Survival curves were compared using the log-rank test. RESULTS: The BPRS total predicted score halved its baseline value in 3 months for bipolar disorder patients, in 6 months for schizoaffective disorder patients, and in 24 months for schizophrenia patients. The proportion of subjects who satisfied the criterion for response to clozapine after 48 months of follow-up was significantly (p <.01) higher in the schizoaffective and bipolar disorder groups (90.0% and 83.8%, respectively) than in the schizophrenia group (64.7%). Baseline scores on the Global Assessment of Functioning (GAF) showed low levels of psychosocial and occupational functioning in all 3 groups. After 48 months of treatment, GAF scores showed a functional improvement in all 3 groups, with significantly (p <.01) greater improvement in the bipolar disorder group compared with the other groups. CONCLUSION: The findings of this study confirm the efficacy and safety of clozapine for treatment-resistant patients with a diagnosis of schizophrenia, schizoaffective disorder, or bipolar disorder with psychotic features. Patients with schizoaffective disorder and those with bipolar disorder show greater clinical improvement than those with schizophrenia. Patients with bipolar disorder have the shortest time to response and the highest psychosocial and occupational functioning levels. Patients with schizoaffective disorder have the lowest treatment discontinuation rate.

Adult↗

PubMed2006

Does the Child Behavior Checklist juvenile bipolar disorder phenotype identify bipolar disorder?

BACKGROUND: A profile of Child Behavior Checklist(CBCL) T-scores>or=70 on the attention problems, aggression, and anxious/depressed subscales has been proposed to identify juvenile bipolar disorder(JBD). We tested this hypothesis in a population-based sample. METHODS: Data for this analysis come from a birth-records-based twin sample having semi-structured interview and CBCL data (N=1,346). We compared prevalence of DSM-IV psychiatric disorders and suicidal behaviors in CBCL-JBD and non-CBCL-JBD subjects. Twin modeling assessed genetic and environmental contributions to CBCL-JBD. Associations with DRD4 and DAT1 were examined using chi-square tests. RESULTS: The prevalence of CBCL-JBD was 2.5%. No subjects with CBCL-JBD met criteria for bipolar or other mood disorders. CBCL-JBD subjects had more oppositional defiant disorder (ODD), conduct disorder(CD), and attention deficit hyperactivity disorder(ADHD). The CBCL-JBD profile was uncommon in these disorders. CBCL-JBD subjects more frequently endorsed suicidal behaviors. The CBCL-JBD profile was heritable and associated with the number of DAT1 9-repeat 3' untranslated region alleles. CONCLUSIONS: The CBCL-JBD phenotype does not correspond with a semi-structured interview assessment of JBD. ADHD, CD, and ODD are common in children with CBCL-JBD but do not account for the profile. Increased suicidal behaviors indicate substantial impairment in CBCL-JBD subjects.

Adolescent↗

PubMed1996

Molecular genetics of bipolar disorder.

Bipolar (BP) disorder is a severe mood disorder affecting about 1% of the population. Even though the traditional twin, family, and adoption studies have demonstrated that it is highly heritable, the specific vulnerability genes have so far escaped identification. The early years of molecular genetic studies in BP disorder were hampered by the complexities in the inheritance and phenotype of BP disorder, the poor marker maps and the low informativeness of DNA markers available at that time. The new developments in molecular genetics and statistical analysis methods for complex disorders have provided researchers with better tools to cope with these difficulties. During the past few years, several potential susceptibility loci have been reported in chromosomes 18, 21 and X, and the possible role of trinucleotide repeat expansions in the aetiology of BP disorder has been developed. It seems that the molecular genetics of BP disorder are entering a new era of rapid developments.

Bipolar Disorder↗

PubMedDate not supplied

The role of lithium clinics in the treatment of bipolar disorder.

Bipolar affective disorder is a serious and enduring mental health problem, which is associated with high mortality rates worldwide. Lithium is a first-rank treatment for this disorder but with its narrow therapeutic range and associated risks of toxicity, careful monitoring of its use is mandatory. Lithium clinics ensure that patients using this therapy have access to appropriate monitoring on a regular basis, providing immediate results for lithium level testing. Clinics also provide support and education, encouraging patients to take responsibility for monitoring the side-effects of their treatment.

Adult↗

PubMed1997

Attention-deficit hyperactivity disorder with bipolar disorder: a familial subtype?

OBJECTIVE: To clarify the nosological status of children with attention-deficit hyperactivity disorder (ADHD) who also satisfy diagnostic criteria for bipolar disorder (BPD). METHOD: Blind raters and structured psychiatric interviews were used to examine 140 children with ADHD, a sample of 120 non-ADHD comparisons, and their 822 first-degree relatives. Data analyses tested specific hypotheses about the familial relationship between ADHD and BPD. RESULTS: After stratifying the ADHD sample into those with and without BPD, the authors found that (1) relatives of both ADHD subgroups were at significantly greater risk for ADHD than relatives of non-ADHD controls; (2) the two subgroups did not differ significantly from one another in their relatives' risk for ADHD; (3) a fivefold elevated risk for BPD was observed among relatives when the proband child had BPD but not when the proband had ADHD alone; (4) an elevated risk for major depression with severe impairment was found for relatives of ADHD + BPD probands; (5) both ADHD and BPD occurred in the same relatives more often than expected by chance alone; and (6) there was a trend for random mating between ADHD parents and those with mania. CONCLUSIONS: The data suggest that comorbid ADHD with BPD is familially distinct from other forms of ADHD and may be related to what others have termed childhood-onset BPD.

Adolescent↗

PubMed2003

Is there a relationship between attention deficit hyperactivity disorder and bipolar disorder?

With the increasing recognition of attention deficit hyperactivity disorder (ADHD) in adults and psychotic disorders in children and adolescents, the possibility of a relationship between bipolar disorder (BP) and ADHD has attracted growing interest. This paper critically reviews the scientific literature concerning this postulated relationship by examining evidence from clinico-epidemiological, follow up, family and laboratory studies, including neuroimaging, neuropsychology and genetic studies. The evidence suggests that although the diagnostic categories of BP and ADHD appear to be unrelated, there is support for a possible relationship between some ADHD and manic-like symptoms. However, several fundamental methodological issues require rectification in future research in order to further elucidate the relationship between these disorders.

Adolescent↗

PubMed2002

Familial links between attention deficit hyperactivity disorder, conduct disorder, and bipolar disorder.

Although family, twin, and adoption studies indicate that attention deficit hyperactivity disorder (ADHD) is a familial condition with a robust genetic component, molecular genetic studies of candidate genes have produced inconsistent findings. One of the challenges to elucidating the genetic architecture of ADHD is its potential genetic heterogeneity. Therefore, efforts are needed to identify etiologically homogeneous subgroups of subjects with ADHD for use in genetic studies. The current article reviews evidence suggesting that parsing ADHD subjects based on comorbidity with conduct and bipolar disorders may yield familial subtypes that are suitable for genetic analyses.

Attention Deficit Disorder with Hyperactivity↗

PubMed1996

Association study of a null mutation in the dopamine D4 receptor gene in Italian patients with obsessive-compulsive disorder, bipolar mood disorder and schizophrenia.

Although serotonergic dysregulation is a leading pathogenetic hypothesis for obsessive-compulsive disorder (OCD), some evidence also suggests a possible dysregulation of the dopaminergic system in this disorder. Therefore, individual differences in deoxyribonucleic acid (DNA) coding for dopamine receptor proteins might contribute to the genetic background of this disorder. Previously we reported a null mutation in exon 1 of the dopamine D4 receptor gene. The variant type is characterized by a 13 bp deletion and is predicted to code for a truncated, non-functional receptor. We assessed the frequency of this polymorphism in 157 OCD patients, 196 schizophrenics, 111 bipolars and 162 healthy controls of Italian descent. Our findings do not implicate a role for this mutation in conferring a susceptibility to OCD and confirm previous negative results regarding its involvement in schizophrenia and bipolar disorder.

Bipolar Disorder↗

PubMed2005

Metabolic syndrome in bipolar disorder: findings from the Bipolar Disorder Center for Pennsylvanians.

OBJECTIVE: This study sought to evaluate the presence of the metabolic syndrome in a group of 171 patients with bipolar disorder who were consecutively recruited in the Bipolar Disorder Center for Pennsylvanians. METHODS: Data were collected from participants entering the Bipolar Disorder Center for Pennsylvanians protocol between 2003 and 2004. The study focused on the presence of the metabolic syndrome, as defined by the National Cholesterol Education Program Expert Panel on Detection, Evaluation And Treatment of High Blood Cholesterol in Adults (NCEP ATP III). RESULTS: Thirty percent of the sample met the NCEP ATP III criterion for the metabolic syndrome, 49% met the criterion for abdominal obesity, 41% met the criterion for hypertriglyceridemia, 48% met the criterion for hypertriglyceridemia or were on a cholesterol-lowering medication, 23% met the criterion for low high-density lipoprotein cholesterol, 39% met the criterion for hypertension and 8% met the criterion for high fasting glucose or antidiabetic medication use. Patients with the metabolic syndrome and patients endorsing the obesity criterion were more likely (p = 0.05 and p = 0.004, respectively) to report a lifetime history of suicide attempt/s. CONCLUSIONS: The prevalence of the metabolic syndrome in patients with bipolar disorder is alarmingly high, as it is for the general population. The prevalence of obesity is even higher than the already very high prevalence that has been estimated for the US general population. Our findings are a reason for concern, considering the difficulty in implementing prevention and treatment programs in the bipolar population. We strongly support the development and testing of interventions specifically designed for preventing and treating the metabolic syndrome and its components in patients with bipolar disorder.

Academic Medical Centers↗

PubMed1997

Panic disorder with familial bipolar disorder.

If bipolar disorder is genetically heterogeneous, it may be possible to discern clinically heterogeneous familial subtypes based on differential risk for psychiatric comorbidity, for example panic disorder. We evaluated 528 members of 57 families ascertained for a genetic linkage study of bipolar disorder. Families were assorted according to the panic disorder diagnosis of the bipolar proband; the rates of panic and other disorders in relatives were compared. Eighty-eight percent of the 41 subjects with panic disorder had bipolar disorder. Panic disorder was diagnosed in 18% of family members with bipolar disorder. Ten of 57 bipolar probands had panic disorder. Their bipolar first-degree relatives had a significantly higher prevalence of panic disorder, bipolar II, cyclothymia, and dysthymia, but had lower prevalence of substance abuse than the relatives of the bipolar probands without panic disorder. These findings suggest the testable hypothesis that comorbid panic disorder is a marker of genetic heterogeneity in bipolar disorder.

Adult↗

PubMed1995

The relationship between substance abuse and bipolar disorder.

The significant prevalence of substance use disorders among patients with psychiatric illnesses has attracted increasing interest. One large epidemiologic study indicates that, of all Axis I disorders, bipolar disorder is the most likely to co-occur with alcohol or drug abuse. Evidence is emerging that shows that bipolar patients who also abuse drugs or alcohol have an earlier onset and worse course of illness compared with those who do not. They are more likely to experience irritable and dysphoric mood states, increased treatment resistance, and a greater need for hospitalization. Caution about diagnosing bipolar disorder in the presence of substance abuse is advised because of overlapping symptomatology. A rationale for the pharmacologic approach to treatment is explored. Data from several studies indicate that the presence of a substance use disorder may be a predictor of poor response to lithium. While it is possible that the anticonvulsants divalproex sodium and carbamazepine may be more useful in this population, a direct comparison of lithium with the anticonvulsants in a substance-abusing population of individuals with bipolar disorder has not yet been performed. Further investigation of diagnostic and treatment issues in this important population of patients with bipolar disorder is needed.

Alcoholism↗

PubMed2006

Immunoreactivity of 43 kDa growth-associated protein is decreased in post mortem hippocampus of bipolar disorder and schizophrenia.

Impairment of neuroplasticity is considered to play a role in the pathogenesis of psychiatric disorders. To further characterize the impairment of neuroplasticity in psychiatric disorders, expression of the neuronal plasticity marker 43 kDa growth-associated protein (GAP-43) was detected in postmortem hippocampal sub-regions from psychiatric patients including major depressive disorder, bipolar disorder and schizophrenia subjects, and matched control subjects. We found that GAP-43 protein levels in the hippocampal hilar region were significantly lower in bipolar disorder and schizophrenia subjects than in control subjects. We also found that GAP-43 protein levels in the inner molecular layer of the dentate gyrus and the stratum radiatum of CA2 region were reduced in a trend in bipolar disorder and schizophrenia subjects when compared with control subjects. These results suggest that impairment of neuroplasticity may occur in the hippocampus of bipolar disorder and schizophrenia patients.

Analysis of Variance↗

PubMedDate not supplied

Strategies for managing depression complicated by bipolar disorder, suicidal ideation, or psychotic features.

BACKGROUND: Major depression, a common clinical problem that, if recognized early and treated vigorously, is often highly responsive to antidepressants and can be complicated by such features as mania, suicidal thoughts and actions, and psychosis. Suicide is one of the most serious complications of major depression. METHODS: An online search of the medical literature was used to select English-language articles addressing depression using, but not limited to, the following specific terms: "primary care," "depressive disorders," "bipolar disorder," "suicide," "psychosis," and "antidepressants." RESULTS AND CONCLUSIONS: Treatment of the manic phases of bipolar disorder includes lithium or anticonvulsants. Breakthrough depression can be particularly resistant to treatment in bipolar patients, and the tricyclic antidepressants can cause patients to cycle more rapidly into the manic phase. The selective serotonin reuptake inhibitors (SSRIs) and bupropion are less likely to cause rapid cycling in bipolar disorder. Depressed patients with suicidal tendencies should be closely monitored and given full doses of antidepressant medications. The SSRIs lessen suicidal tendencies and, importantly, are markedly safer than the tricyclic antidepressants when taken in an overdose. Depressed patients can also become psychotic, exhibiting mood-congruent delusions. Combination therapy with antidepressant and antipsychotic medications is often necessary. Some physicians prefer to hospitalize patients with psychotic depression. Depression can be a complex and multifaceted disorder that requires careful diagnosis and treatment plans.

Antidepressive Agents↗